From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

From Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (R.D.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (F.L.N., A.R.F.); Kidney Research Institute (R.K., B.K., R.A.K.), Division of Cardiology (N.S., K.K.P.), University of Washington, Seattle; Division of Cardiology, Veterans Affairs Medical Center, Minneapolis, MN (S.A.); Division of Cardiology, University of Maryland School of Medicine, Baltimore (C.R.D.); Division of Nephrology, University of Washington, Seattle (B.K.); Division of Cardiology, University of Minnesota Medical School, Minneapolis (L.Y.C., S.K.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.R.H.); Department of Biostatistics (R.A.K.), The New York Academy of Medicine, New York, NY (D.S.); General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA, Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

Dr Karam and colleagues question the absence of atrial fibrillation (AF) from our sudden cardiac death (SCD) prediction model. A prior analysis by Chen et al, also from the ARIC study (Atherosclerosis Risk in Communities) and the CHS study (Cardiovascular Health Study), demonstrated an independent association between AF and SCD. We agree that there are potential electrophysiological reasons for evaluating AF as a risk factor for SCD. Atrial remodeling processes, which are characterized by shorter action potential duration and refractoriness, underlie the mechanisms implicated in AF and may predispose to similar changes in ventricular myocytes. In addition, both AF and SCD can result from myocardial fibrosis or hypertrophy. However, the differences in the statistical methods for these analyses are important in understanding why AF was not selected as a predictor in our multivariable prediction model.

The SCD prediction model was derived by using an agnostic approach. Our methodology evaluated 26 baseline variables in an unbiased fashion. The multivariable prediction model was derived analytically through backward selection, and the final set of independent variables resulted in the greatest efficiency, defined as the model that identified those at SCD risk while minimizing the overall variability. As such, AF did not contribute additionally to the prediction of SCD beyond the 12 variables that were selected. This agnostic selection approach contrasts with the etiolog...

Dr Karam and colleagues question the absence of atrial fibrillation (AF) from our sudden cardiac death (SCD) prediction model. A prior analysis by Chen et al, also from the ARIC study (Atherosclerosis Risk in Communities) and the CHS study (Cardiovascular Health Study), demonstrated an independent association between AF and SCD. We agree that there are potential electrophysiological reasons for evaluating AF as a risk factor for SCD. Atrial remodeling processes, which are characterized by shorter action potential duration and refractoriness, underlie the mechanisms implicated in AF and may predispose to similar changes in ventricular myocytes. In addition, both AF and SCD can result from myocardial fibrosis or hypertrophy. However, the differences in the statistical methods for these analyses are important in understanding why AF was not selected as a predictor in our multivariable prediction model.

The SCD prediction model was derived by using an agnostic approach. Our methodology evaluated 26 baseline variables in an unbiased fashion. The multivariable prediction model was derived analytically through backward selection, and the final set of independent variables resulted in the greatest efficiency, defined as the model that identified those at SCD risk while minimizing the overall variability. As such, AF did not contribute additionally to the prediction of SCD beyond the 12 variables that were selected. This agnostic selection approach contrasts with the etiologic methods by Chen et al, who tested a predefined AF and SCD hypothesis and evaluated AF as a time-dependent variable.

From an electrophysiological standpoint, our model selected the corrected QT interval, which is a direct measure of ventricular refractoriness and was assessed in the baseline electrocardiograms. A longer corrected QT interval may represent some of the same electric alterations that would be suggested by the presence of AF. Furthermore, the low, baseline prevalence of AF in our study (<1%) likely minimized its overall effect on population-based SCD prediction.

In prior work, we derived a SCD prediction model in the HERS study (Heart and Estrogen/Progestin Replacement Study), a cohort of women with coronary heart disease, and implemented a similar backward selection approach. AF was selected as 1 of 6 predictors for the multivariable SCD prediction score in this intermediate-risk population. The underlying coronary heart disease present in all participants from HERS may have strengthened the effect of AF on SCD risk and enhanced its contribution in the final multivariable model. These findings emphasize how models for the same end point can have different variables on the basis of the underlying study population. For this reason, external validation of the final risk score provides insight into the generalizability of the findings to other, similar populations.

In the next letter, Dr Fysekidis and colleagues highlight that body mass index (BMI) was not selected as a predictor in our SCD model. We agree that the risk of SCD increases with the severity of obesity; however, there are a few caveats. First, in our group’s prior work, obesity was associated with SCD only among nonsmokers. Thus, the association between obesity and SCD would be weaker in a nonstratified analysis from the general population. Furthermore, the prevalence of severe obesity in both ARIC and CHS was <5%. As a result, these populations would not be suitable to assess the impact of severe obesity on SCD risk. In addition, as described earlier, our study design and methods used an agnostic approach to identify the set of variables that were predictive of SCD. For the development of prediction models, each variable should be assessed as a linear measure to capture as much information as possible. We had performed spline analysis for each potential variable including BMI to confirm that linear associations with SCD were present. If certain BMI ranges result in a particularly higher or lower risk of SCD, then it is reasonable to pursue a categorical analysis. Otherwise, prediction models should use continuous terms as much as possible to optimize individual precision.

Last, it is possible that waist-to-hip ratio is a better risk factor for SCD than BMI. However, waist-to-hip ratio is not as widely available in clinical practice, and we preferred to use BMI. Future studies should assess whether waist-to-hip ratio should be included in SCD prediction models.

We read with great interest the article by Deo et al regarding the prediction of sudden cardiac death (SCD) in the general population. The authors developed and validated a score for the prediction of SCD in adults without a history of cardiovascular disease based on data from the ARIC (Atherosclerosis Risk in Communities) and the CHS (Cardiovascular Health Study) cohorts. Variables retained in the score were age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval.

We were, however, surprised to note that atrial fibrillation (AF) was not included in the score. The authors of this article were among the first to report a potential causal association between AF and SCD, which has been the subject of some controversy. On the one hand, some data seem to support the notion that AF may increase susceptibility to SCD. Rapid antegrade conduction down an accessory pathway in a patient with Wolff-Parkinson-White syndrome during an episode of AF has been a classical scenario linking AF with SCD, well known for years. However, does AF increase risk for common SCD? Rapid ventricular rates resulting from AF, with consequent reductions in ventricular refractoriness and ventricular short-long-short sequences related to AF, might all favor the emergence of ventricular arrhythmias. Several animal studies,...

We read with great interest the article by Deo et al regarding the prediction of sudden cardiac death (SCD) in the general population. The authors developed and validated a score for the prediction of SCD in adults without a history of cardiovascular disease based on data from the ARIC (Atherosclerosis Risk in Communities) and the CHS (Cardiovascular Health Study) cohorts. Variables retained in the score were age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval.

We were, however, surprised to note that atrial fibrillation (AF) was not included in the score. The authors of this article were among the first to report a potential causal association between AF and SCD, which has been the subject of some controversy. On the one hand, some data seem to support the notion that AF may increase susceptibility to SCD. Rapid antegrade conduction down an accessory pathway in a patient with Wolff-Parkinson-White syndrome during an episode of AF has been a classical scenario linking AF with SCD, well known for years. However, does AF increase risk for common SCD? Rapid ventricular rates resulting from AF, with consequent reductions in ventricular refractoriness and ventricular short-long-short sequences related to AF, might all favor the emergence of ventricular arrhythmias. Several animal studies, and more recently experience from large cohorts of implantable cardioverter defibrillator recipients, have further added to the possibility that AF may facilitate induction of ventricular tachyarrhythmias. Finally, recent studies using magnetic resonance imaging have demonstrated that subjects with lone AF (and normal left ventricular ejection fraction) had evidence of diffuse ventricular structural remodeling with the presence of myocardial fibrosis compared with sinus rhythm patients.

On the other hand, the issue of a causal relationship between AF and SCD is challenging. Notwithstanding the highly significant association between these 2 common entities (even after considering potential confounders), the fact that AF also predicts nonsudden death raises questions about the specificity of the AF–SCD relation; thus, any conclusion that interventions to treat AF would decrease SCD burden would be rather premature. The Oregon-SUDS data (Oregon-Sudden Unexpected Death Study), including both diastolic and systolic heart failure evaluation, revealed that AF–SCD association was mainly driven by the presence of heart failure. The absence of a significant relationship between AF and SCD in the current analysis is probably the result of a more extensive adjustment on confounding factors compared with the data presented in 2012. It also illustrates the low probability that AF is an independent predictor of SCD. The Oregon-SUDS data suggest that AF could be a marker of greater cardiovascular risk rather than being causally related to SCD. Cause of death analyses from large populations of patients with AF indeed show that cardiovascular mortality is the leading cause of death in such populations and that meticulous management of cardiovascular risk factors could improve outcomes. Clearly, further investigation is needed to achieve a deeper and clearer understanding of the interplay among AF, SCD, and congestive heart failure.

In their article, Deo et al produced a useful tool to estimate the risk of sudden cardiac death (SCD) in middle-age and elderly individuals without a clinical diagnosis of cardiovascular disease. Their work is of utmost importance; SCD is a leading cause of death, and its societal burden surpasses any individual cancer and most other leading causes of death.

In the Framingham Heart Study, after 26 years of follow-up, obese (defined by excess metropolitan relative weight) men and women, respectively, had 2.6- and 5.8-fold increased risk of SCD compared with lean individuals. More recently, the ARIC study (Atherosclerosis Risk in Communities), the derivation cohort in Deo et al, found significant association between abdominal obesity, defined by waist-to-hip ratio, and SCD in middle-age, nonsmoking individuals. Waist-to-hip ratio was independently associated with SCD after adjusting for possible mediators and comorbidities.

The precise mechanisms of obesity-associated SCD remain to be elucidated. Proposed mechanisms include morphological changes (cardiomyopathy of the obese and left ventricular hypertrophy) and electrophysiological alterations, such as increased premature ventricular contractions, QT interval prolongation and increased QT dispersion, decreased heart rate variability, and abnormal late potentials. Obesity is also associated with comorbidities, such as obstructive sleep apnea and traditional cardiovascular risk factors like diabetes mellitus, hyp...

In their article, Deo et al produced a useful tool to estimate the risk of sudden cardiac death (SCD) in middle-age and elderly individuals without a clinical diagnosis of cardiovascular disease. Their work is of utmost importance; SCD is a leading cause of death, and its societal burden surpasses any individual cancer and most other leading causes of death.

In the Framingham Heart Study, after 26 years of follow-up, obese (defined by excess metropolitan relative weight) men and women, respectively, had 2.6- and 5.8-fold increased risk of SCD compared with lean individuals. More recently, the ARIC study (Atherosclerosis Risk in Communities), the derivation cohort in Deo et al, found significant association between abdominal obesity, defined by waist-to-hip ratio, and SCD in middle-age, nonsmoking individuals. Waist-to-hip ratio was independently associated with SCD after adjusting for possible mediators and comorbidities.

The precise mechanisms of obesity-associated SCD remain to be elucidated. Proposed mechanisms include morphological changes (cardiomyopathy of the obese and left ventricular hypertrophy) and electrophysiological alterations, such as increased premature ventricular contractions, QT interval prolongation and increased QT dispersion, decreased heart rate variability, and abnormal late potentials. Obesity is also associated with comorbidities, such as obstructive sleep apnea and traditional cardiovascular risk factors like diabetes mellitus, hypertension, and dyslipidemia.

Two points worth discussion in Deo et al include:

1. Despite the presence of epidemiological and mechanistic data, body mass index did not emerge as a predictor in the new SCD prediction model. What about patients with severe obesity? Individuals with a body mass index in the class III obesity range (≥40.0 kg/m2) have substantially higher cardiovascular mortality rates, and they were not included in the model. Class III obesity affected ≈15.5 million adults in the United States in 2010 (or 6.6% of the population).

It seems that the authors evaluated body mass index continuously, not categorically. By doing so, a significant part of the population (individuals with class III obesity) with high risk of SCD is left out of the prediction model. We think that body mass index should have been evaluated after being categorized into classes.

2. Authors did not mention waist-to-hip ratio, which represents the most significant predictor of SCD in the obese. It seems that the authors did not evaluate waist-to-hip ratio in their model.